In recent years, photodynamic therapy (PDT) has emerged as a promising tool in both antiviral and cancer chemotherapy. In the presence of light of the appropriate wavelengths, the photoactive molecule absorbs the light and inactivates the virus or destroys the tumor cell. Photoactive molecules which are currently employed include a mixture of compounds called hematoporphyrin derivatives (HpD), the purpurins and the phthalocyanines. A major drawback is that PDT cannot be extended to treatment in regions of the body where light does not penetrate.
Moan et al., "Yearly Review: Porphyrin Photosensitization and Phototherapy," Photochemistry and Photobiology: Vol. 43, No. 6, pp. 681-690 (1986), which is incorporated herein in its entirety by reference, discloses the tumor localizing property of porphyrins and their use in PDT. The method of treatment involves direct injection of the photosensitizer. The photosensitizer molecules are affected by a light source located outside the body. Moan et al. specifically mention that because penetration of light is limited, PDT can never be used to eliminate large tumors.
Meruelo et al., "Therapeutic Agents With Dramatic Antiretroviral Activity and Little Toxicity at Effective Doses: Aromatic Polycyclic Diones Hypericin and Pseudohypericin," Proc. Natl. Acad. Sci., Vol. 85, pp. 5230-5234 (1988), which is incorporated herein in its entirety by reference, have demonstrated that hypericin inhibits the replication of Friend leukemia virus and radiation leukemia virus, both in vitro and in vivo. Meruelo et al. stated that when hypericin was administered to mice at doses sufficient to prevent retroviral-induced disease, the mice appeared to be devoid of undesirable side effects. Meruelo et al. have also reported that hypericin can reduce the spread of HIV. Meruelo et al. speculate that hypericin may act by direct inactivation of the virions.
Chanh et al., "Photodynamic Inactivation of Simian Immunodeficiency Virus," J. of Virological Methods, Vol. 26, pp. 125-132 (1989), which is incorporated herein in its entirety by reference, disclose photodynamic inactivation of simian immunodeficiency virus (SIV). A dihematoporphyrin ether (DHE) was used to inactivate, in vitro, the infectivity of SIV. DHE was activated through the use of a laser beam. The experiment was conducted by incubating SIV suspended in a culture medium with DHE in the dark, followed by irradiation. The authors postulated that this treatment will reduce the risk of infection by enveloped viruses during transfusions.
Lavie et al., "Studies of Mechanisms of Action of the Antiretroviral Agents Hypericin and Pseudohypericin," Proc. Natl. Acad. Sci., Vol. 86, pp. 5963-5967 (1989), which is incorporated herein in its entirety by reference, disclose that hypericin and pseudohypericin possess anti-retroviral activity. Specifically, the hypericin and pseudohypericin suppress the spread of murine retrovirus in vitro and in vivo. Treatment by hypericin and pseudohypericin resulted in complete inactivation of reverse transcriptase of both murine and human viruses when the compounds were administered by injection.
Hudson et al., "Antiviral Activities of Hypericin," Antiviral Research, Vol. 15, pp. 101-112 (1991), which is incorporated herein in its entirety by reference, disclose that hypericin inactivates murine cytomegalovirus (MCMV) Sindbis Virus, and HIV-1.
U.S. Pat. Nos. 4,898,891, 5,049,589 and 5,047,435 to Lavie et al., all of which are incorporated herein by reference, disclose the antiviral effects of hypericin and pseudohypericin and antiviral pharmaceutical composition containing hypericin as an active ingredient.
Finally, Matthews et al., "Photodynamic Therapy of Viral Contaminants with Potential for Blood Banking Applications," Transfusion, Vol. 28, No. 1, pp. 81-83 (1988), which is incorporated herein in its entirety by reference, disclose PDT for eradicating viral contaminants. The method employs a hematoporphyrin derivative used as the photosensitizer to inactivate an enveloped virus. The method involves extracorporeal plasmaphoresis, i.e., the blood is taken out of the body prior to being treated with hematoporphyrin and light. The method uses visible light.
There is a need to connect an energy source to photoactive molecules so that PDT can be expanded to all regions of the body. There is also a need to provide a method for targeting PDT to viral infected cells or to tumor cells.
Thus, activation of the energy source must be regulated such that activation preferentially occurs in the virus-infected cells or tumor cells. The present invention overcomes the problems in the prior art by employing an energy source which (1) emits energy in a broad band of wavelengths in the range in which the photoactive molecule absorbs and (2) is chemically activated by another chemical, which is regulated to express in the virus-infected or tumor cell. Thus, photoactivation of the photosensitizer is targeted to the virus-infected or tumor cells. The inventors have also developed chemical tethers to connect the energy source and the photoactive molecule. The use of such a tethered compound allows for the in vivo introduction of an internal chemically-activated light source having broad applications in antiviral and tumor therapy.